Alzheimer's disease is characterized by a profound loss of memory. A number of neurotransmitter systems are reported to be diminished with the disease, including acetylcholine (ACh), norepinephrine (NE), dopamine serotonin, certain opioid peptides, somatostatin, and substance P6. Many of these neurotransmitters are likely to play a modulatory role in memory. Long-term synaptic potentiation (LTP) is believed by many investigators to be a cellular substrate for elementary aspects of learning and memory. Recent work in our laboratory has shown that NE, ACh, and zinc modulate LTP at a particular excitatory synapse in the hippocampus, the mossy fiber synapse. It has been suggested that the activity of this synapse plays a role in amnesia or forgetting. Moreover, the mossy fiber pathway appears to be spared in Alzheimer's disease and may even show some proliferation. A reasonable hypothesis would be that drugs that modulate long-term plasticity at this synapse might have some beneficial therapeutic effect in Alzheimer's disease. In fact, certain drugs (i.e., naloxone and aniracetam) that have been used to alleviate some symptoms of the disease have effects on LTP at this synapse. We propose to explore the mechanisms underlying the neuromodulation of mossy fiber LTP by the putative neurotransmitters NE and ACh. Furthermore, we propose to test the hypothesis that opioid peptides and zinc, which are both released from mossy fiber synapses and suggested to play a role in Alzheimer's disease and memory, contribute to the modulation of LTP at this synapse. We will utilize the in vitro hippocampal slice preparation and electrophysiological techniques, including intracellular current and voltage clamping, for our experimental studies. We believe that the results of our experiments will add significantly to our knowledge of the modulation of synaptic plasticity and hopefully will provide a basis for understanding the behavior of the whole animal.